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The Role of Translational Medicine in Optimization of Therapies Targeting the RAS-MAP Kinase Pathway

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Targeted Therapy of Acute Myeloid Leukemia

Part of the book series: Current Cancer Research ((CUCR))

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Abstract

Activation of the RAS-MAP kinase (MAPK) pathway is a common feature in hematological malignancies, including acute myelogenous leukemia (AML). Based on its central role in regulating growth and survival of a broad spectrum of human cancers, much attention has focused in recent years on pharmacologic targeting of the RAS–RAF–MEK–MAPK intracellular signaling cascade. Multiple agents now exist in various stages of clinical development that are capable of effectively inhibiting the downstream kinases in this pathway. The emergence of these agents into the clinical trial arena now allows us to turn our attention to how best to deploy them for maximal therapeutic impact in AML patients. Optimization of these therapies will ultimately depend not only on the availability of promising clinical agents but also on the identification of patients most likely to respond. Toward this goal, technological advances have led to comprehensive molecular profiling of AML samples to facilitate the identification of prognostic biomarkers and insights into the rational design of combination strategies.

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Authors and Affiliations

  1. Translational Oncology Program, University of Michigan, Comprehensive Cancer Center, NCRC, 1600 Huron Parkway, 48109, Ann Arbor, MI, USA

    Judith S. Sebolt-Leopold

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  1. Judith S. Sebolt-Leopold
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Correspondence to Judith S. Sebolt-Leopold .

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  1. Dept. Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michael Andreeff

Conclusion

Conclusion

The RAS-MAPK pathway has been the subject of intense investigation for the development of therapeutic opportunities to impair the progression of a broad range of malignancies including AML. The ultimate clinical utility of agents targeting this pathway will depend on our ability to prospectively select those patients most likely to benefit from this strategy. The relative ease of obtaining pure samples of tumor cells from AML patients will facilitate the design of individualized therapeutic strategies based on the compilation of comprehensive molecular profiling data. We now have the tools to complement genomic analysis with prospective multiplexed evaluation of kinase activation patterns to provide critical information on dominant signaling pathways in individual cancers. These tools will consequently facilitate selection of AML patients most likely to benefit from RAS-MAPK pathway intervention and will further guide the design of combination strategies to potentiate single-agent effectiveness. As we work toward improvement of AML survival rates, we have made great strides in developing the requisite agents and technologies. We are now faced with the challenge of incorporating them into the practice of molecular medicine for greatest therapeutic impact.

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Sebolt-Leopold, J. (2015). The Role of Translational Medicine in Optimization of Therapies Targeting the RAS-MAP Kinase Pathway. In: Andreeff, M. (eds) Targeted Therapy of Acute Myeloid Leukemia. Current Cancer Research. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1393-0_15

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  • DOI: https://doi.org/10.1007/978-1-4939-1393-0_15

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